Brain uptake of intravenously injected 14C-morphine was shown in rats to be related to arterial pH, and to be augmented by alkalosis. The results are consistent with an increased analgesic effect of morphine during alkalosis in man. In rats, acidosis increased penetration of intravascular sodium fluorescein into the eye, at the retinal pigment epithelium. Both morphine and fluorescein effects are consistent with the pH-partition hypothesis for drug entry into the nervous system. Brain uptake of the water soluble anti-cancer drug Melphalan in very low, because the cerebrovascular-permeability area product is close to that of sucrose. A theoretical model relating glucose transport into the brain and brain glucose utilization was developed and applied to hypoglycemic states. Dimethyl sulfoxide, reported to open the blood-brain barrier, was not effective in mice and rats. Osmotic opening of the blood-brain barrier was used in humans to allow anti-neoplastic agents into the brain for treating brain tumors. The blood-brain barrier in rats, following osmotic treatment, recovered more rapidly to larger than to smaller intravascular molecules, suggesting that barrier opening is mediated by a poremechanism. Osmotic treatment increased the permeability of interendothelial tight junctions to intravascular lanthanum. The rate of loss of methotrexate from the brain, following loading in association with osmotic blood-brain barrier opening, was slower than that of sucrose, suggesting cell uptake of the anticancer drug.